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Therapeutic Potential of Curcumin in Major Retinal Pathologies

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Therapeutic Potential of Curcumin in Major Retinal Pathologies Therapeutic potential of curcumin in major retinal pathologies Krishi V. Peddada, A’sha Brown, Vivek Verma & Marcella Nebbioso International Ophthalmology The International Journal of Clinical Ophthalmology and Visual Sciences ISSN 0165-5701 Int Ophthalmol DOI 10.1007/s10792-018-0845-y 1 23 Your article is protected by copyright and all rights are held exclusively by Springer Science+Business Media B.V., part of Springer Nature. This e-offprint is for personal use only and shall not be self-archived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com”. 1 23 Author's personal copy Int Ophthalmol https://doi.org/10.1007/s10792-018-0845-y REVIEW Therapeutic potential of curcumin in major retinal pathologies Krishi V. Peddada . A’sha Brown . Vivek Verma . Marcella Nebbioso Received: 1 September 2017 / Accepted: 29 January 2018 Ó Springer Science+Business Media B.V., part of Springer Nature 2018 Abstract that has been found to be efficacious in preventing and Purpose The retina is continually exposed to free treating a number of inflammatory diseases and radicals from its rich blood supply, numerous mito- neoplastic processes. Curcumin exerts anti-inflamma- chondria, and photons of light which strike its surface. tory, anti-tumor, antioxidant, and VEGF inhibition Most pathological processes that take place in the properties through modulation of numerous biochem- retina, such as inflammation, cell apoptosis, or angio- ical mediators. This makes curcumin particularly genesis, can hence involve free radicals directly or effective in retinal disorders. indirectly. Since inflammatory and oxidative stress Results Curcumin has found a role in slowing, and in pathways underlie retinal pathology, compounds that some cases even reversing, age-related macular degen- address these factors are therefore natural choices for eration, diabetic retinopathy, retinitis pigmentosa, pro- treatment. This review article summarizes and pro- liferative vitreoretinopathy, and retinal cancers. vides commentary on curcumin’s therapeutic potential Conclusions However, studies on curcumin’s effi- use in ophthalmology with principal focus on retinal cacy have been limited mostly to animal studies. dosorders. Moreover, the biomedical potential of curcumin is not Methods Curcumin (diferuloylmethane) is a com- easy to use, given its low solubility and oral bioavail- pound of the Indian spice turmeric (Curcuma longa) ability—more attention therefore has been given to nanoparticles and liposomes. K. V. Peddada Keywords Anti-inflammatory drug Á Antioxidant Department of Ophthalmology, Drexel University, drug Á Anti-tumor drug Á Curcuma longa Á Curcumin Á Philadelphia, PA, USA Retinal diseases A. Brown Emory Eye Center, Emory University, Atlanta, GA, USA Introduction: structural aspects and details V. Verma of curcumin Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE, USA The retina is continually exposed to free radicals from M. Nebbioso (&) its rich blood supply, numerous mitochondria, and Department of Sense Organs, Ocular Electrophysiology photons of light that strike its surface. The outer Center, Sapienza University of Rome, Viale del segment of the rods has a high content of polyunsat- Policlinico 155, 00161 Rome, Italy e-mail: [email protected] urated fatty acids that are particularly sensitive to 123 Author's personal copy Int Ophthalmol peroxidation given their number of double bonds. The transcription factors, which in turn inhibit cellular inner segments of the rods are particularly rich in inflammatory responses and protect cells (Table 1). mitochondria, which contain activated oxygen species There has been a fair amount of work done that may cause damage if they leak out of cells. The assessing curcumin’s potential in ocular pathology. blood supply to the choroid is the richest in the retinal A review by Pescosolido et al. touches on many body, with vertebrate retinas having a sevenfold features that make curcumin a strong therapeutic agent higher rate of oxygen consumption per milligram of in many parts of the eye. Curcumin has found protein than other areas tested. Furthermore, the light application in dry eye syndrome by reducing the that hits the retina may trigger photooxidative pro- inflammation created by increased tear osmolarity. In cesses. Visible light in the blue wavelength forms the animal models of cataracts, curcumin was found to toxic compound A2E which targets cytochrome reduce the free radical damage and calcium influx that oxidase and induces irreversible DNA damage in is responsible for the proteolysis causing clouding of RPE cells. Most pathological processes that take place the lens. In diabetic retinopathy (DR), curcumin was in the retina, such as inflammation, cell apoptosis, or found to improve retinal microcirculation by inducing angiogenesis, can hence involve free radicals directly nitric oxide production. For age-related macular or indirectly [1–3]. degeneration (AMD), curcumin may provide therapy Because inflammatory and oxidative stress path- through beneficial effects on microglial cells that are ways underlie retinal pathology, compounds that responsible for drusen formation [4]. Researchers address these factors are therefore natural choices for have even hypothesized a possible therapeutic effect treatment. One such compound is curcumin (diferu- of the curcumin on protease inhibitors that help loylmethane), the orange and water-insoluble pigment maintain cellular and tissue homeostasis (Table 2) extracted from turmeric. It is derived from the rhizome [5, 6]. Some authors have even theorized a possible of Curcuma longa, a spice that belongs to the therapeutic effect of protease inhibitors in treatment of Zingiberaceae family. Chemically, curcumin incor- neovascularization and inflammation in animal mod- porates several functional groups. The aromatic ring els [5–7]. systems or phenols are connected by two a,b-unsat- In light of its angiogenesis-modulating profile and urated carbonyl groups. The diketones form anti-inflammatory properties, curcumin has great stable enols and are readily deprotonated to form potential in the treatment of inflammatory and neo- enolates; the a,b-unsaturated carbonyl group is a good vascular proliferative diseases of the retina. nucleophilic acceptor of a carbanion or another This article will summarize and provide commen- nucleophile [4]. tary on curcumin’s therapeutic potential with a focus The mechanism by which curcumin induces its on primary retinal disorders. effects is yet to be fully elucidated, but many studies have shown its relevance as a potent anti-inflamma- tory and immunomodulating agent. Curcumin is able Age-related macular degeneration to down-regulate the expression of genes involved in apoptosis, proliferation, and transformation, by AMD is the leading cause of worldwide blindness in inhibiting the nuclear factor jB (NF-jB) activation. the elderly and is projected to cost $59 billion Other studies demonstrated that curcumin may exert worldwide over the next 20 years [8]. It occurs when an anti-inflammatory effect through the activation of extracellular material, known as drusen or lipofuscin, peroxisome proliferator-activated receptor-c (PPAR- builds up between Bruch’s membrane and the retinal c), a group of transcriptional factors that regulate gene pigment epithelium (RPE). AMD may lead to geo- expression. In addition, curcumin inhibits the free graphic atrophy with loss of RPE and photoreceptors radicals production and so exhibits antioxidant prop- and may further progress to wet macular degeneration erties [4]. if new blood vessels bleed into the inner retinal layers. Indeed, curcumin with its pleiotropic activities can Evolving atrophic macular degeneration represents at modulate the expression and activation of many least 80% of all AMD and is currently without an cellular regulatory proteins such as chemokines, accepted treatment regimen [9, 10]. interleukins, hematopoietic growth factors, and 123 Author's personal copy Int Ophthalmol Table 1 Curcumin inhibits or down-regulates a number of biochemical mediators 'Curcumin inhibits directly or indirectly G-proteins Lipo-oxygenase Cyclooxygenase Interleukin-1-6-8 (IL) Tumor necrosis factor-a (TNF-a) Free radicals production (antioxidant properties) Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-jB) 'Curcumin down-regulates directly or indirectly Down-regulate the expression of IjBa gene Down-regulate the expression of prostaglandin E-2 (PGE-2) Down-regulate the expression of genes involved in apoptosis Down-regulate the expression of genes involved in cellular proliferation and transformation Table 2 Molecules most commonly involved in maintaining cellular and tissue homeostasis Proteases and protease inhibitors mainly involved in retinal and uveal diseases Iris and ciliary body SLPI: MMPs: Calpain inhibitor: Endophthalmitis, vitreous and retina disorders SLPI: MMPs: Calpain inhibitor: Angiogenesis, tumor, inflammation, oxidative stress (AMD), and fibrosis SERPINA3
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